Biomedical Sciences Graduate Program(s)
Biomedical Sciences Graduate Programs
Research Description
Research in my laboratory is focused on the development of mouse models for identifying
genes controlling complex human diseases, particularly those resulting from abnormalities
of the immune system. Using both linkage analyses and classical recombinational
genetics, we have localized such genes in three distinct models of autoimmunity,
including insulin-dependent (“juvenile”) diabetes, systemic lupus erythematosus,
and Crohn’s-like inflammatory bowel disease. We are currently using molecular
and computational approaches, as well as detailed studies of immune function,
to define the structural differences in disease-associated alleles and to characterize
their function in both mice and humans.
Type 1 diabetes (T1D):
T1D results from T cell-dependent inflammatory destruction of insulin-producing
pancreatic islet cells. Our studies have shown that the development of full-blown
disease requires sequential expression of defects in antigen presentation to
T cells, control of T cell activation to self antigens from the islets, and
the response of pancreatic islet cells to the resulting local inflammation initiated
by self-antigen-specific T cells. Each step in the disease process can be controlled
by a unique set of genes, resulting in an extremely complicated polygenic susceptibility.
However, disease can be blocked by normalizing gene function at several discrete
steps. We have identified abnormalities in key regulatory genes that control
the differentiation and activation of both CD8+ T cells and myeloid antigen
presenting cell subsets (macrophages and dendritic cells) in non-obese diabetic
(NOD) mice, a well-established model of human T1D. These genes include a member
of the Runt family of transcriptional regulators, as well as key members of
the GM-CSF signaling pathway. Current work in the laboratory seeks to identify
the specific targets of these genes that are required for maintaining normal
tolerance in the T cell population and preventing the development of organ-specific
autoimmune disease. We are also testing whether the same pathways are defective
in human T1D and attempting to identify small molecule inhibitors and activators
of these gene products as potential therapeutic agents.
Systemic lupus erythematosus (SLE):
In SLE, T cells appear to interact with B cells to produce antibodies that recognize
self nuclear polynucleotide/protein antigens. Immune complexes, formed when
such antibodies interact with circulating debris from necrotic or apoptotic
cells, deposit in tissues and induce inflammatory damage in kidneys, skin, and
other target organs. Using the NZM2328 mouse, an inbred model of human SLE,
we have localized two genes which control the development of pathological autoantibodies
and target damage to the kidney. We are currently attempting to identify these
genes by traditional positional cloning methods and by functional characterization
of the effector cell populations.
Crohn’s disease (CD)
We have also completed a genetic analysis of a new spontaneous mouse model of
inflammatory bowel disease, the SAMP1/Yit mouse. Although T lymphocytes may
play a significant role in the initiation or progression of CD, it is clear
that the innate immune system and the intestinal epithelial cells themselves
are the most important factors in the development of this disease, allowing
us to contrast the genetic susceptibility in this disorder with those for SLE
and T1D. We have recently demonstrated that rare variants of the peroxisome
proliferator-activated receptor gamma (PPAR-g) can block genetic predisposition
to Crohn's disease in both humans and mice. PPAR-g has been shown to down-regulate
inflammatory responses, and loss of PPAR-g expression in mouse models is associated
with rapid induction of destructive intestinal inflammation in response to chemical
or immunological damage. Using the SAMP1/Yit mouse, we were able to show that
protective alleles of PPAR-g are characterized by high levels of expression
in the crypts of the small intestine. This tissue contains the essential stem
cell populations for continuous repopulation of the absorptive and protective
mature epithelial cells. We are currently determining the mechanism by which
this crypt-specific expression controls disease susceptibility and investigating
several promising therapeutic strategies for enhancing protective levels in
individuals genetically susceptible to development of CD.
Techniques routinely used in our laboratory include polymerase chain reaction
amplification of DNA (PCR), methods for quantifying gene expression, enzyme-linked
immunosorbant assays (ELISA), flow cytometry, and cell culture, as well as computational
methods for performing linkage analysis and sequence comparisons.
Additional Responsibilities & Affiliations:
Advisor, Medical Microbiology
Pediatric Endocrinology/Diabetes
Director, DERC Mouse Genetics Core
Selected Publications
McDuffie, M., Maybee, N.A., Keller, S.B., Nunemaker, C.S., Morris, M.A., Garmey, J., and Nadler, J.L. 2008. Targeted deletion of 12/15 lipoxygenase markedly reduces the incidence of autoimmune diabetes in non-obese diabetic (NOD) mice. Diabetes. 57:199-208.
Chung, D.D., Honda, K., Cafuir, L., McDuffie, M., and Wotton, D. 2007. The
Runx3 distal transcript encodes an additional transcriptional activation domain. FEBS J. 274:3429-3439.
Litherland, S.A., Grebe, K.M., Belkin, N.S., Paek, E., J. Elf, J., Atkinson, M., Morel, L., Clare-Salzler, M.J., and McDuffie, M. 2005. Nonobese Diabetic Congenic Mouse Analysis of Macrophage STAT5 Dysfunction and GM-CSF Overproduction. J. Immunol. 175:4561-4565.
Sugawara K, Olson TS, Moskaluk CA, Stevens BK, Hoang S, Kozaiwa K, Cominelli F, Ley KF, McDuffie M. Linkage to peroxisome proliferator-activated receptor-gamma in SAMP1/YitFc mice and in human Crohn's disease. Gastroenterology. 2005 Feb;128(2):351-60.
PubMed Listings for this Faculty Member
Intranet Profile
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Office Address: |
PO Box 801390 Aurbach Medical Research Building 450 Ray C, |
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Office Phone: |
+1 434-924-1707, +1 434-924-1267 |
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Fax Phone: |
+1 434-243-9143 |
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